ACS Medicinal Chemistry Letters最新文献_第6页

Structural Preferences and ADMET Regulation of Fluorinated Small-Molecule Drugs 含氟小分子药物的结构偏好和ADMET调控

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-06 DOI: 10.1021/acsmedchemlett.6c00261

Shuai Tao, Lijie Wei, Yichu Wu, Xiang Lian, Jingjing Wu, Yiwei Liu, Fanhong Wu

{"title":"Structural Preferences and ADMET Regulation of Fluorinated Small-Molecule Drugs","authors":"Shuai Tao, Lijie Wei, Yichu Wu, Xiang Lian, Jingjing Wu, Yiwei Liu, Fanhong Wu","doi":"10.1021/acsmedchemlett.6c00261","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00261","url":null,"abstract":"Fluorination is a powerful yet highly context-dependentstrategyin medicinal chemistry. The F-DrugDatabase comprising 1,789 fluorinatedsmall molecules was constructed, including 430 FDA-approved or marketeddrugs. Using Bemis–Murcko scaffold analysis and a matched molecularpair (MMP) “defluorination-hydrogenation” approach,we reveal that 87.7% of fluorinated drugs contain only 1–3fluorine atoms, with benzene scaffolds dominating (63.5%). QuantitativeMMP analysis indicated that the −CF3 group was associatedwith an increase in predicted elimination half-life (average Δt1/2 = +12.24 h, P < 0.01), whereas −CH2F showed less favorable and more variable predicted effects. Basedon these insights, we propose F_RO5, a fluorination-adapted drug-likenessguideline (MW ≤ 800 Da, cLogP ≤ 7, and TPSA ≤200 Å2) that covers 94.2% of marketed fluorinateddrugs, providing broader coverage than the conventional Lipinski Rule-of-Five(68.2%). This data-driven framework provides quantitative guidelinesfor rational fluorination and early stage candidate prioritization.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 8","pages":"1854–1863"},"PeriodicalIF":3.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148718517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Benchmarking Classical and Quantum Machine Learning for Potency Prediction across Ten Therapeutically Relevant Targets 经典和量子机器学习对十个治疗相关目标的效力预测进行基准测试

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-07 DOI: 10.1021/acsmedchemlett.5c00724

Shiv Garg, Sara Garg

{"title":"Benchmarking Classical and Quantum Machine Learning for Potency Prediction across Ten Therapeutically Relevant Targets","authors":"Shiv Garg, Sara Garg","doi":"10.1021/acsmedchemlett.5c00724","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00724","url":null,"abstract":"Quantum machine learning (QML) is widely proposed asa successorto classical models in cheminformatics, but rigorous benchmarks underrealistic contemporary data constraints remain scarce. We comparedtwo quantum classifiers (quantum support vector machine, variationalquantum classifier) against gradient boosting, random forest, andneural network baselines across ten therapeutically diverse proteintargets (45–18,286 compounds), using Bemis–Murcko scaffold-stratifiedcross-validation. Across 48 valid target-threshold tasks, no modelclass globally dominated (best-quantum versus best-classical Wilcoxonp = 0.189). Classical ensembles excelled on data-rich, structurallycoherent targets (e.g., BACE1), while quantum kernels held a marginaledge on sparse, structurally bimodal targets (e.g., Mtb DprE1). Apotential predictor of quantum advantage was the per-target best-quantum/best-classicalmodel Cohen’s κ gap (Spearman ρ = +0.685, p = 0.029),suggesting that decision calibration, not ranking, drives QML’sedge. We propose the κ gap as a preliminary low-cost screeningcriterion for prioritizing QML in early stage discovery campaigns.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 8","pages":"1736–1743"},"PeriodicalIF":3.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification and Studies of Highly Potent and Selective Heterobifunctional Galectin-3 Degraders 高效选择性异双功能半乳糖凝集素-3降解剂的鉴定与研究

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-31 DOI: 10.1021/acsmedchemlett.6c00262

Chunjian Liu, Wei Wang, Aaron J. Balog, Sarah Traeger, Manoranjan Panda, Narasimharaju Kalidindi, Ari Salinger, Yuka Amako, Ashok R. Dongre, Gregory Locke, Fei Yu, John A. Newitt, Susan E. Kiefer, Joseph Naglich, Dong Cheng, Harinath Sale, Bruce A. Ellsworth, Alicia Regueiro-Ren

{"title":"Identification and Studies of Highly Potent and Selective Heterobifunctional Galectin-3 Degraders","authors":"Chunjian Liu, Wei Wang, Aaron J. Balog, Sarah Traeger, Manoranjan Panda, Narasimharaju Kalidindi, Ari Salinger, Yuka Amako, Ashok R. Dongre, Gregory Locke, Fei Yu, John A. Newitt, Susan E. Kiefer, Joseph Naglich, Dong Cheng, Harinath Sale, Bruce A. Ellsworth, Alicia Regueiro-Ren","doi":"10.1021/acsmedchemlett.6c00262","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00262","url":null,"abstract":"On the basis of an X-ray cocrystal structure of our previouslydisclosed monosaccharide-derived galectin-3 inhibitor 3 with human galectin-3 protein, we envisioned that galectin-3 couldbe an appropriate target for targeted protein degradation as a potentialnovel drug discovery strategy. The identification and studies of aseries of potent, metabolically stable, cell permeable, and noncytotoxicgalectin-3 degraders, represented by 5 and 6, are herein reported. These compounds were highly effective in inducinggalectin-3 degradation in normal human lung fibroblast (NHLF), A549,and LL29 cells with a degradation half effective concentration (DC50) value of 4 nM for 5 in NHLF cells. Globalproteomics analysis of 6 revealed that the galectin-3degrader was exquisitely selective for galectin-3 over >7800 otherproteins quantified that include galectin family members. To the bestof our knowledge, targeted protein degradation of galectin-3 or anyother lectin has not been reported in the past.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 8","pages":"1864–1872"},"PeriodicalIF":3.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

HTS-Oracle X: AI-Guided Prospective Discovery of Small Molecule Immune Checkpoint Binders HTS-Oracle X：人工智能引导的小分子免疫检查点结合物的前瞻性发现

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-14 DOI: 10.1021/acsmedchemlett.6c00289

Somaya A. Abdel-Rahman, Moustafa Gabr

{"title":"HTS-Oracle X: AI-Guided Prospective Discovery of Small Molecule Immune Checkpoint Binders","authors":"Somaya A. Abdel-Rahman, Moustafa Gabr","doi":"10.1021/acsmedchemlett.6c00289","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00289","url":null,"abstract":"Targeting immune checkpoint protein–protein interactions(PPIs) using small molecules remains limited by the characteristicallylow hit rates of conventional high-throughput screening against theseinterfaces. Here we report HTS-Oracle X, a multimodal deep learningplatform that integrates bidirectional cross-attention fusion of ChemBERTaSMILES embeddings with extended RDKit descriptors, trains on continuousbiophysical binding signals rather than binary labels, and employsMonte Carlo Dropout uncertainty quantification for uncertainty-adjustedcompound selection. Trained on 45,760 Dianthus TRIC-screened compoundsper target under scaffold-aware cross-validation, HTS-Oracle X wasapplied prospectively to a 100,160-compound enamine library againstCD28, TIM-3, and VISTA. From 150 model-selected compounds, 45 dose–responseconfirmed binders were identified, yielding enrichment factors of234–408× over experimentally established random prospectivebaselines and 16 sub-micromolar hits. The top hits, HX-CD28-1 (KD = 233 nM), HX-TIM3-1 (KD = 249 nM), and HX-VISTA-1 (KD = 345 nM), demonstrated on-targetfunctional activity in immune cell and tumor coculture assays.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 8","pages":"1888–1894"},"PeriodicalIF":3.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Novel 6,5-Bicyclic Compounds as 5-HT2A Receptor Agonists for Treating Depression, Anxiety, Substance Abuse, and Headaches 新型6,5-双环化合物作为5-HT2A受体激动剂治疗抑郁、焦虑、药物滥用和头痛

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-03 DOI: 10.1021/acsmedchemlett.6c00354

Ram W. Sabnis, Anika R. Sabnis

引用次数: 0

Design, Synthesis, and Evaluation of Diphenylpyrazinyl Amino Cycloalkoxy Acetic Acids as IP Receptor Agonists 二苯基吡嗪基氨基环烷氧基乙酸作为IP受体激动剂的设计、合成和评价

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-20 DOI: 10.1021/acsmedchemlett.6c00241

Xianrong Cai, Minhui Dai, Yuhe Wang, Guiying Liu, Xiaoli An, Xiulan Li, Yi Huang, Zhenqiang Mu, Qingquan Fu, Yingwei Wang

{"title":"Design, Synthesis, and Evaluation of Diphenylpyrazinyl Amino Cycloalkoxy Acetic Acids as IP Receptor Agonists","authors":"Xianrong Cai, Minhui Dai, Yuhe Wang, Guiying Liu, Xiaoli An, Xiulan Li, Yi Huang, Zhenqiang Mu, Qingquan Fu, Yingwei Wang","doi":"10.1021/acsmedchemlett.6c00241","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00241","url":null,"abstract":"To address the pharmacokinetic limitations and moderatepotencyof current prostanoid IP receptor agonists for treating pulmonaryarterial hypertension, we developed a series of conformationally constraineddiphenylpyrazinyl amino cycloalkoxy acetic acids. By replacing theflexible side chain of MRE-269 with a rigid cyclic framework, we lockedthe bioactive conformation, identifying 7a-5 and itsdeuterated analog 7a-19. Compound 7a-19 exhibitedpotent antiaggregatory activity (IC50 = 0.97 μM),a 7-fold enhancement over MRE-269 (IC50 = 7.4 μM).Crucially, leveraging the deuterium kinetic isotope effect in rats, 7a-19 demonstrated an 11-fold increase in systemic exposure(AUCo-t = 26.7 h μg/mL),a prolonged half-life (t1/2 = 12.0 h),and excellent oral bioavailability (F = 47.3%). Combinedwith a clean safety profile in the Mini-Ames assay and a lack of hERGinhibition (IC50 = 143.1 μM), 7a-19 standsout as a robust, long-acting lead candidate for PAH therapy.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 8","pages":"1826–1834"},"PeriodicalIF":3.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148718490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synthesis and Structural-Activity Relationship Analysis of 7-Deazaadenosine-Based BTK Inhibitors as Potent Antiplatelet Agents 7-去氮腺苷类BTK抑制剂的合成及构效关系分析

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-01 DOI: 10.1021/acsmedchemlett.6c00125

Jieun Kim, Jung Hoon Park, Taeryeong Kim, Lak Shin Jeong, Tong-Shin Chang

{"title":"Synthesis and Structural-Activity Relationship Analysis of 7-Deazaadenosine-Based BTK Inhibitors as Potent Antiplatelet Agents","authors":"Jieun Kim, Jung Hoon Park, Taeryeong Kim, Lak Shin Jeong, Tong-Shin Chang","doi":"10.1021/acsmedchemlett.6c00125","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00125","url":null,"abstract":"Targeting glycoproteinVI (GPVI) signaling via Bruton’styrosine kinase (BTK) inhibition represents a promising antiplateletstrategy with minimized bleeding risk. We developed a novel seriesof 5′-modified 7-substituted 7-deazaadenosine derivatives asirreversible BTK inhibitors. Structure–activity relationshipstudies identified that the 4-phenoxyphenyl moiety at the 7-positioneffectively occupied the hydrophobic pocket, while flexible electrophilicwarheads, particularly 2-chloroacetamide, at the 5′-positionenhanced both covalent BTK inhibition and antiplatelet activity. Notably,the α-lyxo configuration provided superior cellular target engagementover conventional β-ribo counterparts. The lead compound 19b (L-α-lyxo, 5′-chloroacetamide) exhibitedexceptional BTK inhibitory potency (IC50 = 6 nM) and potentinhibition of collagen-induced platelet aggregation (IC50 = 16 nM). Targeting GPVI signaling via BTK inhibition representsa promising antiplatelet strategy with the potential to reduce bleedingliability. These findings establish 19b as a promisinglead compound for the development of GPVI-BTK pathway-targeted antiplateletagents with a potentially improved bleeding profile.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 8","pages":"1756–1765"},"PeriodicalIF":3.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148718512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Systems-Driven Identification and Experimental Validation of Actinomycetes-Derived Secondary Metabolites as Promising Antileishmanial Agents Targeting Leishmania donovani Methionyl-tRNA Synthetase 针对多诺瓦利什曼原虫甲硫基trna合成酶的放线菌衍生次级代谢物的系统驱动鉴定和实验验证

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-02 DOI: 10.1021/acsmedchemlett.6c00201

Satyendra Singh, Kirti Baghel, Preshita Bhalerao, Tarun Kumar Bhatt, Dhaneswar Prusty, Vijay Kumar Prajapati

{"title":"Systems-Driven Identification and Experimental Validation of Actinomycetes-Derived Secondary Metabolites as Promising Antileishmanial Agents Targeting Leishmania donovani Methionyl-tRNA Synthetase","authors":"Satyendra Singh, Kirti Baghel, Preshita Bhalerao, Tarun Kumar Bhatt, Dhaneswar Prusty, Vijay Kumar Prajapati","doi":"10.1021/acsmedchemlett.6c00201","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00201","url":null,"abstract":"Visceral leishmaniasis (VL) , caused mainly by Leishmania donovani in the Indian subcontinent, remains a major healthconcern due to the limited treatment options. This study aims to identifyantileishmanial compounds from StreptomeDB 3.0, a database of Streptomycetes-derived secondary metabolites. High-throughputvirtual screening (HTVS) of 6,524 compounds against 17 validated drugtargets identified three multitargeting hits. Among them, oxytetracyclineshowed the highest potency against L. donovani promastigotes(IC50 of 2.71 μM), comparable to the known antileishmanialdrug miltefosine (IC50 = 2.13 μM). The cytotoxicityevaluation on J774A.1 murine macrophage cells yielded a selectivityindex of 32.65, underlining its safety profile. To elucidate its modeof action, we investigated the binding affinity of oxytetracyclinewith L. donovani methionyl-tRNA synthetase (LdMetRS)using Bio-Layer Interferometry (BLI), which suggested a binding affinity(Kd) of 23.7 μM. Furthermore, amalachite green functional assay showed oxytetracycline inhibits LdMetRS,(IC50 = 6.63 μM). These results confirm LdMetRS asone of the targets for oxytetracycline. This study highlights oxytetracyclineas a promising repurposed lead for VL using an integrative in-silico screening, phenotypic screening, and biochemicaltarget validation.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 8","pages":"1816–1825"},"PeriodicalIF":3.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148718513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting Streptococcus mutans Antigen I/II To Inhibit Dual-Species Biofilms with Candida albicans 针对变形链球菌抗原I/II抑制白色念珠菌双种生物膜

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-27 DOI: 10.1021/acsmedchemlett.6c00275

B. Owen Garrett, Parvathy Babu, Bhavitavya Nijampatnam, Abhishek Govindan, Norbert Schormann, Manisha Patel, Gregory Harber, Suzanne M. Michalek, Hui Wu, Champion Deivanayagam, Sadanandan E. Velu

{"title":"Targeting Streptococcus mutans Antigen I/II To Inhibit Dual-Species Biofilms with Candida albicans","authors":"B. Owen Garrett, Parvathy Babu, Bhavitavya Nijampatnam, Abhishek Govindan, Norbert Schormann, Manisha Patel, Gregory Harber, Suzanne M. Michalek, Hui Wu, Champion Deivanayagam, Sadanandan E. Velu","doi":"10.1021/acsmedchemlett.6c00275","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00275","url":null,"abstract":"We employed structure-based drug design to target theV-regionof Streptococcus mutans antigen I/II (VAgI/II) and identified inhibitors of S. mutans (SM) – C. albicans (CA) dual-species biofilms. The lead compound, SN195, inhibited SM single-species biofilms and SM–CA dual-species biofilms at IC50 values of 49.9 and 23.6μM, respectively, without affecting the planktonic growth ofeither microbe. SN195 at 100 μM did not affectthe growth of the tested oral commensals. The X-ray cocrystal structureof SN195 bound to VAgI/II revealed crucialinteractions in the vicinity of the conserved Ca2+ ionin the binding pocket. Structure activity relationship studies resultedin the development of more potent dual-species biofilm inhibitors, 1b and 1j, with IC50 values of 12.9μM and 0.41 μM, respectively. In a dual-species gnotobioticrat caries model coinfected with SM and CA, treatment with SN195, 1b,or 1j significantly reduced buccal and sulcal cariesscores compared to infected and untreated control rats.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 8","pages":"1878–1887"},"PeriodicalIF":3.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148718515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeted Degradation of CDK2: A New Strategy for Overcoming Cyclin E-Driven Cancers 靶向降解CDK2：克服细胞周期蛋白e驱动的癌症的新策略

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-12 DOI: 10.1021/acsmedchemlett.6c00362

Anna C. Renner, Robert B. Kargbo

引用次数: 0